It is estimated that nearly one-third of all individuals in the United States will develop cancer. While early diagnosis and treatment of this disease has increased the five year relative survival rate to nearly 50%, cancer remains second only to cardiac disease as the leading cause of death; approximately 20% of Americans die from cancer each year.
Cancer cells (also referred to as neoplastic or malignant cells) can be defined in terms of four characteristics as to which they differ from normal cells. "Clonality" refers to the fact that most cancer originates from a single stem cell which proliferates to form a clone of malignant cells. "Autonomy" refers to the fact that the growth of malignant cells is not properly regulated by normal biochemical and physical influences in the environment. "Anaplasia" refers to the lack of normal, coordinated cell differentiation which characterizes malignant cells. "Metastasis" is the characteristic capacity of cancer cells for discontinuous growth and dissemination to other parts of the body.
While each of these characteristics can be expressed by normal, non-malignant cells at certain appropriate times during development, cancer cells exhibit these characteristics in an inappropriate or excessive manner. Many approaches to the diagnosis and treatment of cancer have sought to take advantage of these characteristic differences. In particular, many forms of cancer demonstrate unusual sensitivity to radiation and chemotherapy. In addition to, or in combination with, traditional surgical excision, gains in treatment of cancers, including acute leukemia, lymphoproliferative malignancies, testicular and breast cancer, have been realized.
Limitations of these forms of treatment, including undesirable side effects, have lead medical investigators to seek new treatment modalities, including immunotherapy. Malignant cells are sufficiently different from normal cells to be recognized and destroyed by the immune system.
One approach to immunotherapy against tumors exploits cytolytic T lymphocytes (CTL), which are key immune cells in the body believed to direct the attack on cancer cells. The basis of this approach is that the identification of tumor cell-specific antigens not found on normal cells should lead to the generation of CTL capable of attacking and lysing the cells which make up a cancerous tumor. (See, e.g., Boone, T., et al., Ann. Rev. Immunol. 12:337-65 (1994); Van Pel, A., et al., Immunol. Rev. 145:229-250 (1995); Boone, T., et al., Immunol. Today 16:334-36 (1995)).
Investigators have also recognized, however, that in many instances, known tumor cell specific antigens are insufficiently immunogenic to bring about CTL activation. Accordingly, some have looked to generate a cellular immune response in patients (i.e., to achieve vaccination against cancer) by presenting the patient's immune system with the putative antigen, together with an adjuvant, such as the B7 protein and various cytokines including interleukin-2 and interferon .gamma., granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4. (See, e.g., Rosenberg, A., J. Clin. Oncol. 10:180-199 (1992); Marchand, M., et al., Dermatol. 186:278-280 (1993); Marchand, M., et al., Rnt. J. Cancer 63:883-85 (1995)). A number of tumor cell-specific antigens, including MAGE-1, MAGE-3, and MART for melanoma and E6 and E7 for human papillomavirus (HPV)-associated cervical carcinoma, are in preliminary human clinical trials.
It is also known that CTL recognize tumor cell-specific antigens which are presented by Major Histocompatibility Complex (MHC) Class I glycoproteins. These glycoproteins, along with MHC Class II glycoproteins, immunoglobulins and T cell receptors (TCRs), make up families of antigen binding molecules responsible for specificity, repertoire and memory in the immune response. Although the somatic rearrangement of their immunoglobulin or TCR genes restricts individual B and T cells to a single specificity for antigen, millions of specificities are possessed by the immune system as a population of cells. Immunoglobulin receptors on B cells bind to native protein antigens, whereas TCRs recognize short peptide fragments bound by polymorphic MHC glycoproteins. Diverse species, ranging from cattle to chickens to amphibians to humans, have an MHC region. The human MHC, known as the Human Leukocyte Antigen (HLA) region, is located on the short arm of chromosome 6. Because of its importance in self/non-self discrimination for tissue transplantation in humans, the bulk of knowledge about the MHC region has come from studies on human and murine MHCs.
The size and other physical characteristics of MHC Class I peptides and the structural basis for their direct binding to MHC Class I glycoproteins has been elucidated based on crystallographic studies of the HLA-A2 molecule. (See, e.g., Engelhard, V. H., Ann. Rev. Immunol. 12:181-207 (1994)), and investigators have attempted to achieve vaccination against cancer cells by injecting such peptides (Id.; Marchand, M., et al., Int. J. Cancer 63:883-85 (1995)). However, this approach is also subject to the limitations described above for other vaccination methods.
Accordingly, there exists a need for methods and compositions for the therapeutic treatment of cancer in patients suffering therefrom which would overcome or obviate the limitations of available approaches.